Treatment of HIV-1 infection with multidrug therapies can delay AIDS, but these multidrug cocktails also sometimes fail for a variety of reasons. There is still a great need for the development of new antiviral agents which are selective for unique targets. The two retroviral zinc finger motifs of the HIV-1 nucleocapsid p7 (NCp7) protein may prove to be such unique antiviral targets since they are conserved among all known retroviruses. The first specific aim of this proposal is the preparation of new sulfur heterocycles which will chemically modify the nucleophilic cysteine residues in the NCp7 zinc fingers. All new heterocycles produced will be screened in collaboration with Dr. William Rice (Laboratory of Antiviral Drug Mechanisms, Frederick Cancer Research Center & Achillion Pharmaceuticals). New compound synthesis and active compound binding will be guided by and studied via molecular modelling techniques in the laboratory of Dr. David Covell at the NCI-Frederick Center. Nine of the heterocycles the investigators have synthesized to date are active in their XTT cytoprotection anti-HIV-1 assay and most are also zinc ejectors (NCp7 Trp37 assay). Two are anti-HIV-1 active at concentrations (6 mM) which are lower than the best five or six membered ring sulfur compounds (NSC 661126 & 624151) they have screened to date from NCI's chemical repository. Here the applicants propose to chemically modify the active compounds with the goal of maintaining anti-HIV-1 activity and reducing toxicity. The second specific aim of this proposal is the study of the reaction chemistry of anti-HIV-1 active compounds with glutathione and cysteine. It is clear from Dr. Rice's earlier studies that the competing cellular thiolate nucleophile, glutathione, can alter anti-HIV-1 activity and zinc ejecting ability of these compounds. Susceptibility or lack thereof to thiolate anion attack on their compounds could be a preliminary screen, and determination of the structures of the chemically modified compounds could provide models for the chemical modification that is occurring at the cysteine residues in the zinc fingers. Isolable thiolate conjugates would also be subjected to the battery for screens described in Specific Aim 1.